Glutamic acid is an excitatory neurotransmitter that is widely present in the brain. The first indication of its role as an excitatory messenger emerged in the 1950's, when it was observed that intravenous administration of glutamate induces convulsions. However, the detection of the entire glutamatergic neurotransmitter system, with biosynthetic and catabolic enzymes, cellular uptake mechanisms, intracellular storage and release systems, and its cell-surface ion channels and G protein-coupled receptors, did not take place until the 1970's and 1980's, when suitable pharmacological tools were first identified. It was in the 1990's that the newly emergent tools of molecular biology provided means for the molecular identification and classification of glutamatergic ion channels, receptors, transporters, etc.
The membrane-bound ion channels that are gated by the excitatory amino acids glutamate and glycine, and that also respond to the xenobiotic compound N-methyl-D-aspartate (NMDA), control the flow of both divalent and monovalent cations into pre- and post-synaptic neural cells (see Foster et al., Nature 1987, 329:395-396; Mayer et al., Trends in Pharmacol. Sci. 1990, 11:254-260). They are molecularly, electrophysiologically, and pharmacologically distinct from the glutamate-gated, cation-conducting ion channels that respond to the xenobiotic agents kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA); and they are similarly distinct from the family of glutamate-gated G protein-coupled receptors, the so-called metabotropic glutamate receptors.
The NMDA-preferring glutamate-gated ion channel has a hetero-tetrameric structural basis: two obligatory GluN1 units and two variable GluN2 receptor subunits encoded by the GRIN1 gene and one of four GRIN2 genes, respectively. One or both GluN2 subunits can be potentially replaced by a GluN3A or a GluN3B subunit. The GRIN1 gene product has 8 splice variants while there are 4 different GRIN2 genes (GRIN2A-D) encoding four distinct GluN2 subunits. The glycine binding site is present on the GluN1 subunit and the glutamate binding site is present on the GluN2 subunit (Paoletti P et al., Nat Rev Neurosci. 2013; 14(6):383-400).
Multiple classes of positive or negative allosteric modulators of glutamate-gated ion channels have been described; they bind glutamate-gated ion channels at the inter-subunit interface of the ligand-binding domains (LBD's) of the respective ion channels, a site that is distinct from the glutamate- or the glycine-binding sites present within the LBD (Sun et al., 2002; Jin et al., 2005; Hackos et al., 2016). Allosteric modulators have also been described (Wang et al. 2017) that bind to the trans-membrane domain of the NMDA-type glutamate-gated ion channel, where a highly-conserved structural motif (the so-called “Lurcher domain”) restricts ionic flow through the pore when the ion channel is in the closed or deactivated state (Karakas and Furukawa, 2014; Lee et al., 2014; Ogden and Traynelis, 2013).
Allosteric modulators of glutamate-gated ion channels have therapeutic potential, and even utility in healthy individuals, in diverse fields, such as learning, memory processing, mood, attention, emotion, motoneuron disease, peripheral sensory neuropathy and pain perception (Cull-Candy S et al., Curr Opin Neurobiol. 2001; 11(3):327-35).
Compounds that modulate NMDA receptor function can be useful in treatment of many neurological and psychiatric disorders including but not limited to bipolar disorder (Martucci L et al., Schizophrenia Res, 2006; 84(2-3):214-21), major depressive disorder (Li N et al., Biol Psychiatry. 2011; 69(8):754-61), treatment-resistant depression (Preskorn S H et al. J Clin Psychopharmacol. 2008; 28(6):631-7) and other mood disorders (including schizophrenia (Grimwood S et al., Neuroreport. 1999; 10(3):461-5), ante- and postpartum depression (Weickert C S et al. Molecular Psychiatry (2013) 18, 1185-1192), seasonal affective disorder, and the like; Alzheimer's disease (Hanson J E et al., Neurobiol Dis. 2015; 74:254-62; Li S et al., J Neurosci. 2011; 31(18):6627-38) and other dementias (Orgogozo J M et al. Stroke 2002, 33: 1834-1839), Parkinson's disease (Duty S, CNS Drugs. 2012; 26(12):1017-32; Steece-Collier K et al., Exp Neurol. 2000; 163(1):239-43; Leaver K R et al. Clin Exp PharmacolPhysiol. 2008; 35(11):1388-94), Huntington's chorea (Tang T S et al., Proc Natl Acad Sci USA. 2005; 102(7):2602-7; Li L et al., J Neurophysiol. 2004; 92(5):2738-46), multiple sclerosis (Grasselli G et al., Br J Pharmacol. 2013; 168(2):502-17), cognitive impairment (Wang D et al. 2014, Expert Opin Ther Targets 2014; 18(10):1121-30), head injury (Bullock M R et al., Ann NY Acad Sci. 1999; 890:51-8), spinal cord injury, stroke (Yang Y et al., J Neurosurg. 2003; 98(2):397-403), epilepsy (Naspolini A P et al., Epilepsy Res. 2012 June; 100(1-2):12-9), movement disorders (e.g. dyskinesias) (Morissette M et al., Mov Disord. 2006; 21(1):9-17), various neurodegenerative diseases (e.g. amyotrophic lateral sclerosis (Fuller P I et al., Neurosci Lett. 2006; 399(1-2):157-61) or neurodegeneration associated with bacterial or chronic infections, glaucoma (Naskar R et al. Semin Ophthalmol. 1999 September; 14(3):152-8), pain (e.g. chronic, cancer, post-operative and neuropathic pain (Wu L J and Zhuo M, Neurotherapeutics. 2009; 6(4):693-702), diabetic neuropathy, migraine (Peeters M et al., J Pharmacol Exp Ther. 2007; 321(2):564-72), cerebral ischemia (Yuan H et al., Neuron. 2015; 85(6):1305-18), encephalitis (Dalmau J. et al., Lancet Neurol. 2008; 7(12):1091-8.), autism and autism spectrum disorders (Won H. et al., Nature. 2012; 486(7402):261-5), memory and learning disorders (Tang, Y. P. et al., Nature. 1999; 401(6748):63-9), obsessive compulsive disorder (Arnold P D et al., Psychiatry Res. 2009; 172(2):136-9.), attention deficit hyperactivity disorder (ADHD) (Dorval K M et al., Genes Brain Behav. 2007; 6(5):444-52), PTSD (Haller J et al. Behav Pharmacol. 2011; 22(2):113-21; Leaderbrand K et al. Neurobiol Learn Mem. 2014; 113:35-40), tinnitus (Guitton M J, and Dudai Y, NeuralPlast.2007; 80904; Hu S S et al. 2016; 273(2): 325-332), sleep disorders (like narcolepsy or excessive daytime sleepiness, patent WO 2009/058261 A1), vertigo and nystagmus (Straube A. et al., Curr Opin Neurol. 2005; 18(1):11-4; Starck M et al. J Neurol. 1997 January; 244(1):9-16), anxiety, autoimmunological disorders like neuropsychiatric systemic lupus erythematosus (Kowal C et al. Proc. Natl. Acad. Sci. U.S.A. 2006; 103, 19854-19859) and addictive illnesses (e.g. alcohol addiction, drug addiction) (Nagy J, 2004, Curr Drug Targets CNS Neurol Disord. 2004; 3(3):169-79.; Shen H et al., Proc Natl Acad Sci USA. 2011; 108(48):19407-12).
The symptoms of peripheral sensory neuropathy, including one of the most prominent symptoms, peripheral neuropathic pain (Zilliox L A, 2017), are frequently encountered clinical conditions: the prevalence in the general population has been estimated to be between 7% and 10% (van Hecke O et al., 2014). In the United States, painful diabetic peripheral neuropathy alone is estimated to affect approximately 10 million people. Peripheral sensory neuropathy is often resistant to treatment and is associated with poor patient satisfaction of their treatment. Several medications have been shown to be effective in treating peripheral sensory neuropathy associated with diabetic neuropathy and post-herpetic neuralgia, and these medications are often used to treat neuropathic pain associated with other conditions as well. These treatments often have unwanted adverse effects and discontinuation of treatment may be problematic. It is important to recognize that peripheral sensory neuropathy affects many aspects of daily life and is associated with poor general health, reduction in quality of life, poor sleep, and higher anxiety and depression. In fact, measures of quality of life in people with chronic peripheral sensory neuropathy were rated as low as for patients with clinical depression, coronary artery disease, recent myocardial infraction, or poorly controlled diabetes mellitus (Smith B H et al., 2007).
The American Academy of Neurology has published practice guidelines on the treatment of painful diabetic neuropathy (Bril V et al., 2011), post-herpetic neuralgia (Dubinsky R M et al., 2004), and trigeminal neuralgia (Gronseth G et al., 2008). Several other clinical practice guidelines for the treatment of neuropathic pain also have been published (Attal N et al., 2010; Moulin D, et al., 2014).
Sensory neuropathy is commonly classified as central or peripheral, depending on the site of the lesion that is causing the symptoms. Examples of conditions associated with peripheral sensory neuropathy are diabetic neuropathy, human immunodeficiency virus-associated neuropathy, chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, compressive mononeuropathies, radiculoneuropathies, inflammatory neuropathies (acute and chronic inflammatory demyelinating polyneuropathy), post-traumatic neuropathy, or phantom limb neuropathy.
Typically, peripheral sensory neuropathy has both positive and negative symptoms. Positive symptoms include tingling (“pins and needles”), prickling, lightening-like or lancinating sensations, aching, knife-like, pulling or tightening-like symptoms, burning- or searing-like, or electrical pain. Negative symptoms include numbness, deadness, or the feeling of wearing socks. Some unique aspects of peripheral sensory neuropathy include hyperalgesia (an increased response to a stimulation is normally painful); allodynia (pain due to a stimulus that typically does not provoke pain); hyperesthesia (an increased sensitivity to stimulation); paresthesia (abnormal sensation, whether provoked or spontaneous); dysesthesia (unpleasant abnormal sensation); hypoesthesia (diminished pain in response to a normally painful stimulus); analgesia (loss of pain sensation); and anaesthesia (loss of sensation). The positive signs or symptoms are thought to represent excessive activity in a sensory pathway due to a lowered threshold or heightened excitability. Negative signs and symptoms are experienced as diminished or absent feeling and are due to a loss of sensory function.
While some pharmacological agents have been found to be effective in the treatment of symptoms of peripheral sensory neuropathy (Finnerup N B et al., 2015), only a minority of patients suffering from neuropathic pain show a complete response to drug therapy. For the majority of patients, it is reasonable to expect that treatment will make the pain tolerable. In general, a 30% reduction of a pain on an 11-point numerical rating scale is considered clinically important and constitutes “moderate relief” or “much improved.” It is also important to recognize and treat comorbidities, such as anxiety and depression, and secondary treatment goals may include improving sleep, advancing function, and enhancing overall quality of life. These goals are best achieved when pharmacologic therapy is one component of a multi-disciplinary approach to treatment.
Neuropathic pain medications approved by the US Food and Drug Administration are carbamazepine, duloxetine, pregabalin, gabapentin, topical lidocaine, and topical capsaicin. Tramadol and opioid analgesics are effective in different types of neuropathic pain but are generally not recommended as first-line treatments because of concerns about long-term safety. However, they are recommended as first-line treatments in acute neuropathic pain, neuropathic pain due to cancer, and episodic exacerbations of severe neuropathic pain. The use of strong opioids (codeine, morphine, oxycodone and fentanyl) in the treatment of a variety of neuropathic pain conditions is controversial and a public health concern given the rising number of deaths related to prescription opioids. The serious risks of overdose, dependence, and addiction which these drugs carry may outweigh the potential benefits.
Thus, there remains an urgent and important medical need for the development of novel, orally-effective therapies for peripheral sensory neuropathy and peripheral neuropathic pain that are toxicologically benign and devoid of the potential for dependence and addiction phenomena.
There also remains an important medical need for the development of novel, orally-effective therapies for neuropsychiatric diseases, such as those described in the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); and for the treatment of motoneuron diseases, such as amyotrophic lateral sclerosis.
Dimiracetam (2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole—IUPAC name: (RS)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione) is a bicyclic 2-pyrrolidinone derivative and a nootropic member of the racetam family:

AU 2012/201853 discloses the use of dimiracetam, or a pharmaceutically acceptable solvate thereof, alone or in association with other active principles, in the manufacture of a medicament useful for the treatment and/or prevention of chronic pain.
WO 93/09120 relates to certain processes for preparing certain fused imidazole derivatives and in particular for preparing chiral fused imidazole derivatives.
U.S. Pat. No. 5,200,406 mentions that dimiracetam may be useful in restoring learning and treating memory difficulties. One example of a disease to be treated with dimiracetam is Alzheimer's disease.
Dimiracetam was originally developed as a cognition enhancer and has been shown to be able to improve learning and memory in rats (Pinza M et al., 1993; EP 3 354 83). In single-dose healthy human volunteer studies (Torchio L et al., 1995), dimiracetam was found to ameliorate, versus placebo, certain measures of the transient decline in cognitive performance induced by injection of scopolamine. Further medical uses of dimiracetam have been described including in particular its broad efficacy in rodent models of neuropathic pain. The efficacy of dimiracetam in the treatment of neuropathic pain of different origin has been documented in established models of neuropathic pain induced by nerve injury, chemotherapy, or mono-iodoacetate (MIA)-induced osteoarthritis (Fariello R et al., 2014); Di Cesare Mannelli L et al., 2015a; Di Cesare Mannelli L et al., 2015b; WO 2008/125674; EP 2 857 017 B1, US 2010/0125096; WO 2012/055057). The chemotherapy-induced symptoms of neurotoxicity are responsive to dimiracetam, regardless of which chemotherapeutic agent is used: dideoxycytidine- (ddC-), oxaliplatin-, vincristine-, paclitaxel-, and sorafenib-derived models all respond to the effects of dimiracetam; and dimiracetam has been shown to be effective not only in treating, but also in preventing the symptoms brought on by administration of these chemotherapeutic agents. A single oral administration of dimiracetam can completely, but transiently, revert hyperalgesia and allodynia back to the level of healthy controls. With repeated twice-daily oral administration, the maximal effect becomes sustained, without evidence of tachyphylaxis, or tolerance, despite dose diminution and increased inter-dose interval to once-daily oral administration. Furthermore, the effects of dimiracetam are disease-specific: in a unilateral chronic constriction injury (CCI) model, where rats develop a state of peripheral neuropathic pain in one hind-limb subjected to surgical placement of a ligature around the sciatic nerve, but not in the other limb subjected to sham surgery, a single oral dose of dimiracetam reduced the pain response only in the nerve-ligated limb, without affecting algesia or allodynia in the sham-operated limb; this profile is markedly distinct from effects of, for example, opiates, which affect both limbs in this model (Christensen D et al., 1998).
The mechanism of dimiracetam's pharmacological actions have been explored using synaptosomal preparations of the hippocampus and the spinal cord. This assay is intended to pharmacologically mimic the physiological process of glutamate-triggered glutamate release; its pH-, Zn2+- and ifenprodil-sensitivities suggest involvement of an NMDA-receptor isoform containing pH-sensitive GluN1 and GluN2A subunits (Fariello et al., 2014). Inhibition of glutamate signaling is an established basis for the prevention or the treatment of neuropathic pain (Latremoliere and Woolf, 2009). In the spinal cord, at the junction where peripheral sensory afferents make their first and only synaptic connection to the interneurons of the central nervous system (Marieb, Wilhelm and Mallat, 2017), glutamate-induced glutamate release is a component of the up-regulated, or “sensitized” signaling which results from a damaged peripheral nerve (Latremolier and Woolf, 2009).
In synaptosomal preparations of the hippocampus, dimiracetam is a moderately potent inhibitor with an IC50 of approximately 3 μM for inhibiting NMDA-plus-glycine-triggered release of [3H]-D-aspartate previously loaded into the synaptosomal preparation. In synaptosomal preparations of the spinal cord, however, dimiracetam is much more potent, with an IC50 of approximately 20 nM for inhibiting the NMDA-plus-glycine-triggered [3H]-D-aspartate release (Fariello R et al., 2014).
Dimiracetam's ability to block glutamate-triggered glutamate release in the spinal cord underlies its utility in the prevention or treatment of peripheral sensory neuropathies; other mechanisms in the brain may underlie its efficacy in the treatment of depression in rats (Fariello et al., 2011; WO 2015/010217); and its efficacy in rat and human models of scopolamine-induced cognitive impairment (Pinza et al., 1993).
Dimiracetam is a chiral compound with a single stereocenter, but it has undergone clinical development as a racemic mixture of its (R)- and (S)-enantiomers. This was done even though (R)-dimiracetam is the more active enantiomer (WO 2008/125674), because the racemate of dimiracetam has been found to be even more potent than either of the single enantiomers. For example, in rats pre-treated with 2′,3′-dideoxycytidine (ddC, zalcitabine), a single oral dose of (R)-dimiracetam resulted in partial efficacy response, while the (S)-enantiomer resulted in a smaller response than the corresponding dose of the (R)-enantiomer. On the other hand, racemic dimiracetam gave a superior response compared to either (R)- or (S)-dimiracetam alone (WO 2008/125674). This rank order of potency of (S)-, (R)-, and racemic dimiracetam is also seen in the effect of dimiracetam on reverting MIA-induced hyperalgesia (WO 2008/125674).